LXR and PPARgamma mediated Abeta clearance mechanisms

描述（由申请人提供）：该申请的重点是开发针对核受体、肝X受体（LXRs）和过氧化物酶体增殖物激活受体（pparty）的阿尔茨海默病（AD）的新治疗方法。我们证明，用LXR激动剂治疗老年AD动物模型（Tg2576）可降低A -肽水平和斑块负荷。我们发现LXR激动剂清除大脑A¿的能力依赖于ApoE。重要的是，我们证明了一个全新的机制，通过ApoE促进A¿肽的蛋白水解降解。LXR激活导致ApoE和脂质转运体ABCA1的转录诱导。ABCA1是ApoE通过脂化实现功能成熟所必需的，从而导致含有ApoE的高密度脂蛋白样颗粒的形成，这些颗粒是大脑中胆固醇和磷脂运输所必需的。A¿与ApoE高亲和力结合，这种相互作用受ApoE脂化状态的控制。我们发现脂化形式的ApoE促进了小胶质细胞通过网络溶素依赖的蛋白水解对A -肽的细胞内降解。此外，我们证明脂化ApoE的行为伴随胰岛素降解酶的细胞外降解A¿。相反，脂化程度低的ApoE形成稳定的蛋白酶抗性复合物。重要的是，相关核受体PPARy的激动剂可以引起类似的效果，我们假设PPARy与LXR参与一个积极的、自我强化的反馈回路，以刺激ApoE脂化和a¿清除。这些数据证实了ApoE以前未被认识到的作用，促进了a¿从大脑的蛋白水解清除，这可能是其参与AD发病机制的基础。我们建议建立LXR激动剂治疗的治疗参数，以预防和逆转AD动物模型中AD相关斑块病理的发展。我们将通过检查LXRs基因失活的AD小鼠模型来验证LXRs作为治疗靶点。我们将建立LXRs和pparty靶基因（主要是ApoE和ABCA1）促进A¿清除的机制。我们将测试缔约方在A¿clearance上的行动是否次于LXR功能，并依赖于LXR功能。

DESCRIPTION (provided by applicant): This application is focused on the development of new therapeutic approaches to Alzheimer's disease (AD) that target the nuclear receptors, liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPARy). We demonstrate that treatment of an aged animal model of AD (Tg2576) with LXR agonists results in the reduction of A¿ peptide levels and plaque load. We show that the ability of LXR agonists to clear A¿ from the brain is reliant upon ApoE. Importantly, we demonstrate an entirely novel mechanism through which ApoE facilitates the proteolytic degradation of A¿ peptides. LXR activation results in the transcriptional induction of ApoE and the lipid transporter ABCA1. ABCA1 is required for the functional maturation of ApoE through its lipidation, leading to the formation of ApoE-containing HDL-like particles that are required for cholesterol and phospholipid trafficking in the brain. A¿ binds to ApoE with high affinity and this interaction is governed by the lipidation status of ApoE. We show that lipidated forms of ApoE facilitate the intracellular degradation of A¿ peptides by microglia through neprilysin- dependent proteolysis. Further, we demonstrate that the lipidated ApoE acts to chaperone the extracellular degradation of A¿ by insulin degrading enzyme. In contrast, poorly lipidated forms of ApoE form stable, protease resistant complexes. Importantly, agonists of the related nuclear receptor PPARy can elicit similar effects and we hypothesize that PPARy participates in a positive, self reinforcing, feed back loop with LXR to stimulate ApoE lipidation and A¿ clearance. These data establish a previously unrecognized action of ApoE, facilitating the proteolytic clearance of A¿ from the brain that may underlie its participation in AD pathogenesis. We propose to establish the therapeutic parameters for LXR agonist treatment to prevent and to reverse the development of AD-related plaque pathology in an animal model of AD. We will validate the LXRs as a therapeutic target by examination of murine models of AD in which LXRs have been genetically inactivated. We will establish the mechanisms through which the LXRs and PPARy target genes, most prominently ApoE and ABCA1, to facilitate A¿ clearance. We will test if the actions of PPARy on A¿ clearance are secondary to, and reliant upon, LXR function.